virtual histology; clinical applicability · cardiovascular research foundation asan medical center...

CardioVascular Research Foundation Asan Medical Center

DukDuk--Woo Park, MD, PhDWoo Park, MD, PhD

Virtual Histology; Virtual Histology; Clinical ApplicabilityClinical Applicability

Wrapping Up Current Clinical Study Wrapping Up Current Clinical Study and Future Study Programand Future Study Program

Asan Medical Center, Seoul, Korea


Fibrous; Fibrofatty; Necrotic core; Dense calcium

In-vivo characterization of plaque composition via advanced spectral analysis

Virtual Histology Virtual Histology --IVUSIVUS


Potential VH-IVUS Application in Clinical Field

•• Risk stratification Risk stratification •• PCI outcomes: acute and longPCI outcomes: acute and long--term term •• Plaque vulnerability Plaque vulnerability •• Surrogate marker in systemic Surrogate marker in systemic

therapytherapy


Additional usefulness of VH-IVUS for risk prediction

• Known risk factors - each of established risk factors for CAD- risk score system (Framingham and Score)

• Abnormal lipid profiles • Multiple biomarkers

“VH findings are well correlated with established risk factors predicting cardiovascular events”


Fibrocalcific lesions

Fibrous cap atheroma

Thin cap fibroatheroma

Pathological intimal thickening

0

1020

30

4050

60

70

8090

100

low riskFramingham

(n=8)

intermediate riskFramingham

(n=18)

high riskFramingham

(n=12)

Patie

nts

(%) p=0.03

0

10

20

30

40

50

60

70

80

90

100

low risk SCORE(n=11)

high risk SCORE(n=15)

Patie

nts

(%) p=0.02

Relationship between cardiovascular risk as predicted by established risk scores and coronary artery plaque composition as detected by IVUS-VH analysis

Ahmed A. Khattab, MDDirector, cardiac catheterization

laboratories. Bad Segeberg - Germany

“VH-IVUS Plaque Composition in non-obstructive CAD and Different Risk Scores”

The PREDICT Pilot Study


Global VH RegistryTotal enrollment of 3002 patients

in 42 interventional cardiology centers in the USA, Europe, and Japan

between August 2004 and July 2006 First

Interim Analysis of 990 patients

Global VH RegistryTotal enrollment of 3002 patients

in 42 interventional cardiology centers in the USA, Europe, and Japan

between August 2004 and July 2006 First

Interim Analysis of 990 patients

**The aim of the registry was to determine the clinical and laboratorialcorrelates for VH-IVUS parameters of the culprit lesions


FibrosisFibrosis

FibroFibro--fattyfatty

NecrosisNecrosis

CalciumCalcium

Mea

n %

of P

laqu

e Vo

lum

e

40%

35%

30%

25%

20%

15%

10%

5%

0%

7%

6%

5%

4%

3%

2%

1%

0%

Mea

n %

of P

laqu

e Vo

lum

e

Mea

n %

of P

laqu

e Vo

lum

e

35%

30%

25%

20%

15%

10%

5%

0%

VH-IVUS plaque composition according to age and sex


Mea

n %

of P

laqu

e Vo

lum

e

8%

6%

4%

0%

Mea

n %

of P

laqu

e Vo

lum

e

8%

6%

4%

2%

0%

35%

30%

25%

20%

15%

10%

5%

0%

Mea

n %

of P

laqu

e Vo

lum

eM

ean

% o

f Pla

que

Volu

me 30

%

20%

10%

0%

VH-IVUS plaque composition and Known risk factors and CAD history


VH-IVUS plaque composition and risk factors for SCD in men (n=473)

*TC/HDL levels were independently associated with SCD in men on histopathology study. *Unstable plaque had larger NC/DC ratio on VH study.

Missel, et al. EHJ 2008;29:2141-7


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

1 - Specificity

Sens

itivi

ty

No discrimination NC/Ca ratio % of NC vol % of Ca vol

NC/DC ratio (AUC: 0.64, p<0.0001) over %DC (AUC: 0.58, p=0.006) or %NC (AUC: 0.51, p=0.43) : a pathology-related risk profile for

sudden cardiac death in MEN (TC/HDL>5 and/or smoking).

Missel, et al. EHJ 2008;29:2141-7


VH-IVUS plaque composition and high-risk non-ST elevation ACS

(n=225)*percentage of NC and its ratio to DC in diseased coronary segments are positively associated with a high-risk ACS presentation with positive cardiac enzyme.

Missel, et al. AJC 2008;101:573-8


VH-IVUS plaque composition and serum biomarkers in ACS (n=50)

*Strong association between biomarkers (serum hs-CRP and adiponectin) and %necrotic core in ACS

Otake, et al. AJC 2008;101:1-7

Hs-CRP Adiponectin


• Current VH data showed good correlation between plaque composition with previous histology findings, known and established risk factors, and multiple biomarker for CAD and ACS.

• VH findings beyond clinical risk factors may provide prognostic utility for risk prediction.

“Additional usefulness of VH-IVUS for risk prediction for cardiovascular events”

Brief Summary


Potential VH-IVUS Applicability in Clinical Field

•• Risk stratification Risk stratification •• PCI outcomes: acute and longPCI outcomes: acute and long--term term •• Plaque Vulnerability Plaque Vulnerability •• Surrogate marker in systemic Surrogate marker in systemic

therapytherapy


Potential VH-IVUS Application improving PCI outcomes

• Optimal Lesion coverage • Impact on short-term PCI results

: distal embolization • Impact on long-term PCI results

: ??


Possible site of min LD(Angiographic culprit) (Ruptured TCFA – true culprit)

VH-IVUS-guided lesion coverage

A VH-IVUS Analysis from the PROSPECT Study

“High-risk FAs are usually proximal to the site of the MLA approximately 6±10mm”

Rupture of TCFA (true culprit) and thrombotic tails (angiographic culprit)

CardioVascular Research Foundation Asan Medical CenterCourtesy of Dr. Mark Wholey

Largest NC area

Lack of clinical data comparing VH-IVUS guided vs. angiography/conventional IVUS guided PCI

Impact on:

- Distal embolization

- Stent thrombosis

- Restenosis

- Plaque progression

What is optimal complete lesion coverage?

Angiography or IVUS-guided

VH-IVUS-guided


ThrombosisThrombosis

MicroembolizationMicroembolization

InfarctletsInfarctlets Coronary reserveCoronary reserve

ArrhythmiasArrhythmias DysfunctionDysfunction

Plaque fissuringPlaque fissuring

Plaque rupturePlaque rupture

Erbel and Heusch, J Am Coll Cardiol 39:22-24 (2000)

VH-IVUS predict distal embolization


Usefulness of virtual histology intravascular ultrasound to predict distal embolization for ST-segment elevation myocardial infarction

OBJECTIVES: We aimed to predict the high-risk plaque of distal embolization after stent deployment in patients with acute ST-segment elevation myocardial infarction (STEMI) with Virtual Histology intravascular ultrasound (VH-IVUS) (Volcano Therapeutics, Inc., Rancho Cordova, California).

BACKGROUND: Distal embolization during primary percutaneous coronary intervention (PCI) carries a poor prognosis in patients with STEMI. However, it is unclear which plaque characteristics cause distal embolization after stent deployment.

METHODS: A total of 71 patients with STEMI were included prospectively. All patients underwent primary PCI within 12 h of symptom onset. After crossing the lesion with a guidewire and performing thrombectomy with an aspiration catheter, VH-IVUS of the infarct-related vessel was performed. Stent deployment was then undertaken without embolic protection. ST-segment re-elevation (STR) was used to evaluate distal embolization. Correlations among plaque characteristics, morphology, and distal embolization were analyzed.

RESULTS: The STR after stent deployment was observed in 11 patients (STR group, 15.5%). Necrotic core volume was significantly higher in the STR group than in the non-STR group (32.9 +/- 14.1 mm3 vs. 20.4 +/- 19.1 mm3, p < 0.05). Total plaque volume was similar in both groups. On receiver-operating characteristic analysis, necrotic core volume clearly predicted STR after stent deployment as compared with fibrous, fibro-lipid, dense calcium, and total plaque volumes. The necrotic core volume that was best predictive for STR was 33.4 mm3, with a sensitivity of 81.7% and a specificity of 63.6%.

CONCLUSIONS: Virtual Histology IVUS is a useful means of predicting the risk of distal embolization after primary stent deployment in patients with STEMI.

Kawaguchi R, Oshima S, Jingu M, Tsurugaya H, Toyama T, Hoshizaki H, Taniguchi K.

J Am Coll Cardiol. 2007 Oct 23;50(17):1641-6.


0.04420.4±19.232.9±14.1Necrotic core0.5599.6±13.912.2±8.6Dense calcium0.36813.2±11.49.8±10.4Fibro-lipid0.92068.2±35.367.1±30.7Fibrotic0.636111.4±69.2122.0±57.5Total plaque volume

PNon-STR

(n=60)STR

(n=11)Parameters (volume; mm3)

VH parameters & STR after Primary Stenting for STEMI

**STR (ST-segment Re-elevation) represents distal embolization

Kawaguchi, et al. JACC. 2007;50:1641-6


Angiographic no-reflow phenomenon and plaque characteristics by virtual histology intravascular ultrasound in patients with acute myocardial infarction.

Nakamura T, Kubo N, Ako J, Momomura S. Cardiovascular Division, Jichi Medical University, Omiya Medical Center, Saitama, Japan. Journal of Interv Cardiol 2007; 20:335-9

Objective: This study aimed to evaluate the relationship between the occurrence of the angiographic no-reflow phenomenon in patients with acute myocardial infarction (AMI) and the preintervention plaque composition as assessed by virtual histology intravascular ultrasound (VH-IVUS).

Background: The angiographic no-reflow phenomenon is an adverse prognostic factor in patients with AMI. Method: We enrolled consecutive 50 patients with ST-elevation AMI was treated by primary stent implantation. All culprit lesions were imaged by VH-IVUS before stent implantation. The angiographic no-reflow phenomenon was defined as a decrease in final TIMI flow grade compared with TIMI flow grade before stent implantation.

Results: Eight of 50 patients developed angiographic no-reflow after stent implantation. Gray-scale intravascular ultrasound (IVUS) showed significantly larger external elastic membrane volume and plaque burden in the no-reflow group. VH-IVUS showed a trend toward larger percentage of fibro-fatty plaque volume in the no-reflow group than in the reflow group (23.1 +/- 3.5 vs. 17.0 +/- 1.1%, P = 0.05). The presence of "marble"-like image, mainly consisting of fibro-fatty and fibrous plaque (plaque volume of fibro-fatty + fibrous >80% and containing fibro-fatty plaque volume >10%) was associated with angiographic no-reflow (P = 0.02). Corrected TIMI frame counts of the cases with "marble"-like image were significantly larger than the cases without it (46.8 +/- 5.6 vs. 27.4 +/- 2.3, P = 0.01).

Conclusion: The culprit lesions with large plaque burden, or with "marble"-like image by VH-IVUS, are associated with the angiographic no-reflow phenomenon in patients with AMI.

(1) the plaque volume of fibro-fatty + fibrous >80%; and (2) fibro-fatty plaque >10% of total plaque


0.1313 (72.2)16 (50.0)ST-resolution: >50%

0.0127.4 ± 2.346.8 ± 5.6Corrected TIMI frame counts

0.2613 (72.2)18 (56.2)Myocardial blush grade: 0, 1

0.020 (0)8 (25.0)Angiographic no-reflow

P

Without "Marble"-Like

Appearance (n = 18)

With "Marble"-Like

Appearance (n = 32)

Comparison between Patients with and without "Marble"-Like Appearance

Nakamura et al. J Interv Cardiol. 2007;20:335-9


The relationship between coronary plaque characteristics and small embolic particles during coronary stent implantation

OBJECTIVES: We investigated the relationship between coronary plaque components and small embolic particles during stenting and examined the influence on the coronary microcirculation.

BACKGROUND: In vivo tissue characterization of atherosclerotic plaques was introduced by the Virtual Histology intravascular ultrasound (VH-IVUS) system (Volcano Therapeutics, Inc., Rancho Cordova, California).

METHODS: The study consisted of 44 patients who underwent elective coronary stenting. Plaque characteristics were identified with VH-IVUS, and small embolic particles liberated during stenting were detected as high-intensity transient signals (HITS) with a Doppler guidewire. Coronary flow velocity reserve (CFVR) was also measured before and after stenting.

RESULTS: Patients were divided into the tertiles according to the HITS counts: the lowest, HITS <5 (n = 16); the middle, 5 to 12 (n = 15); and the highest, >12 (n = 13). Dense calcium and necrotic core area identified with VH-IVUS were significantly larger in the highest tertile (lowest vs. middle vs. highest; dense calcium: 0.2 +/- 0.3 mm2 vs. 0.3 +/- 0.6 mm2 vs. 0.8 +/- 0.7 mm2, p = 0.007; necrotic core: 0.5 +/- 0.4 mm2 vs. 0.9 +/- 0.9 mm2 vs. 1.8 +/- 1.0 mm2, p < 0.001, respectively). Multivariate logistic regression analysis revealed only necrotic core area was an independent predictor of high HITS counts (odds ratio 4.41, p = 0.045). Furthermore, there was a significant negative correlation between the HITS count and CFVR after stenting (r = -0.35, p = 0.017).

CONCLUSIONS: The necrotic core component identified with VH-IVUS is related to liberation of small embolic particles during coronary stenting, which results in the poorer recovery of CFVR.

Kawamoto T, Okura H, Koyama Y, Toda I, Taguchi H, Tamita K, Yamamuro A, Yoshimura Y, Neishi Y, Toyota E, Yoshida K.J Am Coll Cardiol. 2007 Oct 23;50(17):1635-40


Independent predictors of the highest HITS count tertile by multivariate analysis

0.0451.03-18.814.41Necrotic core, mm2

0.8040.22-7.211.25Dense calcium, mm2

0.7880.17-3.900.81P+M CSA, mm2

0.8130.25-5.731.21EEM CSA, mm2

p95% CIOR

Kawamoto, et al. JACC. 2007;50:1635-40


0.0221.06–1.721.14Necrotic core area at the largest NC area site

0.041.01–1.021.01Balloon-to-artery ratiop95% CIOR

Independent Correlates of post-PCI CK-MB elevation

Planar VH-IVUS measurements were performed at 2 lesion segments

(minimum lumen cross-sectional area and the largest of necrotic core).

VH-IVUS Measurements

Minimal lumen CSA

Largest necrotic core burden

AMC Clinical Experiences and AMC Clinical Experiences and correlation, n=332 lesionscorrelation, n=332 lesionsDistal Embolization

Duk-Woo Park, MD and Seung-Jung Park, MD.Asan Medical Center, Seoul, Korea

• Acute myocardial infarction • Elevated baseline CK-MB levels• Saphenous vein graft intervention • Long lesions >30mm• Total occlusions• Severe angulations• Heavily calcified lesions

Exclusion criteria


Long-Term VH-IVUS data

• However, there is lack of long-term data assessing preprocedure and postprocedure VH-IVUS findings on long-term clinical events after PCI (death, MI, rehospitalization of unstable angina, or revascularization)


• Find the origin of the problem (the culprit of the culprit) and large NC area

• Assess the risk of plaque protrusion• Assess the risk of distal embolization, stent

underexpansion, and the need for appropriate lesion preparation (densely calcified necrotic core and fibrofatty rich lesions)

VH-IVUS findings on PCI outcomes

Brief Summary




therapytherapy


Plaque Vulnerability and Remodelling

• Plaques with positive remodeling- Are more often rich with pathologic

vulnerable plaque - Have more clinical events during follow-up

(TLR, Death and MI).- They represent the “active plaques”.- Inflammation may play an important role.


Coronary artery remodelling is related to plaque composition

in vivo plaque composition and morphology assessed by spectral analysis of IVUS radiofrequency data were related to coronary artery remodelling.

Rodrigurez-Granillo, et al. Heart 2006;92:388-391 Fujii, et al. Am J Cardiol 2005;96:1476-83


VH-TCFAThree-vessel IVUS Study

Clustering of Ruptured Plaque and Thin-Cap Fibroatheroma: A 3-Vessel Virtual

Histology Intravascular Ultrasound Analysis in 212 Patients

Hong et al. Am J Cardiol 2008;101:568-572


0

20

40

60

80

Rupturedplaque

VH-TCFA non-VH-TCFA

ACS (n=105) SAP (n=107)(%)

10

31

6151

9

38

Culprit lesions

p<0.001, ACS vs. SAP


0

20

40

60

80

Rupturedplaque

VH-TCFA non-VH-TCFA

ACS (n=105) SAP (n=107)(%)

48

69

45

23

51

Non-culprit lesions

p<0.001, ACS vs. SAP


Distance (mm) from ostium

0

10

20

30

40

50

60

70

VH-TCFA in ACS (n=262)VH-TCFA in SAP (n=177)

0 10 20 30 40 50 60 70 80 90

No. of lesions24%

23%

17%

19%27%

29%

11%

19%

Axial distribution of VH-TCFA


F/U: 1 mo, 6 mo, F/U: 1 mo, 6 mo, 1 yr, 2 yr, 1 yr, 2 yr, ±±33--5 yr5 yr

(event driven)(event driven)Repeat imagingRepeat imaging

in pts with events in pts with events

Meds recMeds rec’’ddAspirinAspirinPlavix 1yrPlavix 1yrStatinStatinRepeat biomarkersRepeat biomarkers@ 30 days, 6 months @ 30 days, 6 months

Proximal 6Proximal 6--8 8 cm of each cm of each coronary coronary

arteryartery

MSCTMSCTSubstudySubstudyN=50N=50--100100

700 pts with ACS 700 pts with ACS 11--2 vessel CAD 2 vessel CAD undergoing PCIundergoing PCI

Culprit artery, followed byCulprit artery, followed bynonnon--culprit arteriesculprit arteries

Angiography, IVUS, Angiography, IVUS, VHVH--IVUS, and IVUS, and PalpographyPalpography

The PROSPECT TrialThe PROSPECT Trial


PROSPECT: Imaging SummaryVH of VH of IVUS detectedIVUS detected lesionslesions

7.0%

60.2%

20.5%

12.3%

Dense calcium FibroticFibrofatty Necrotic core

7.0%

60.2%

20.5%

12.3%

Dense calcium FibroticFibrofatty Necrotic core

Virtual histology (N=693)Virtual histology (N=693)-- Mean plaque compositionMean plaque composition--

4.3%- Multiple, + Ca

3.3%- Multiple, - Ca

4.8%- Single, + Ca

6.8%- Single, - Ca

19.2%

23.8%

43.0%

42.9%

8.5%

5.6%

N=681

Fibrotic

- TCFA

- Thick cap

Fibroatheroma

PIT

Fibrocalcific

Plaque subtype


N lesions/pt per coronary treeN lesions/pt per coronary tree

PROSPECT: Imaging Summary

65.6%

18.7%

2.9% 1.2%11.6%

0%

25%

50%

75%

100%

% p

ts w

ith V

H-T

CFA

lesi

ons

0 1 2 3 ≥4

65.6%

18.7%

2.9% 1.2%11.6%

0%

25%

50%

75%

100%

% p

ts w

ith V

H-T

CFA

lesi

ons

0 1 2 3 ≥4

Per pt incidence of VHPer pt incidence of VH--TCFAsTCFAs

34.4% of pts have 34.4% of pts have ≥≥1 VH1 VH--TCFATCFAMean 0.56 Mean 0.56 ±± 0.9 VH0.9 VH--TCFAs per ptTCFAs per pt

Range 0 Range 0 –– 5 per pt5 per ptTotal 135 lesions In 241 ptsTotal 135 lesions In 241 pts


• Plaque vulnerability assessed by VH-IVUS correlated well with clinical vulnerability (AMI>UA>SA)

• VH IVUS data correlates with known sites for plaque accumulation and ruptures.

• More data are needed to assess the relationship between current vulnerability by VH-findings and future coronary events.

VH-IVUS findings on vulnerable plaque

Brief Summary




therapytherapy


Cutlip et al. Circulation 2004; 110: 1226–1230.

Optimal PCI5-year outcomes after stenting: HCRI database

Cumulative Non-target Lesion Event rate

Cumulative non-target lesion event rate is higher than target lesion re-stenosis rate with DES


(One or two vessel disease)

VH-IVUS for non-target vessel(s)

Randomization

Fluvastatin (60mg/day) group(N=35)

Control group(N=35)

Restudy of VH-IVUS after 12 months

Reject of Medication

Hyperlipidemia?(T-cho > 220 mg/dl, or TG > 160 mg/dl, or LDL-cho > 140

mg/dl)YES NO

Stable AP patients with informed consent

Effect of Fluvastatin on progression of coronary atherosclerotic plaque evaluated by intravascular ultrasound Virtual Histology

Kenya Nasu, M.D., Toyohashi Heart Center, AHA 2007


Serial VH IVUS FU

Ave. Fibrous CSA, mm2

BaselineFollow-upAve. Fibro-fatty CSA, mm2

BaselineFollow-upAve. Necrotic CSA, mm2

BaselineFollow-upAve.Dense calcium CSA, mm2

BaselineFollow-up

3.18±1.502.38±1.30*

1.51±0.830.68±0.52*

0.50±0.450.51±0.33

0.18±0.160.24±0.20

2.46±1.203.34±1.41*

0.97±0.441.32±0.84*

0.43±0.280.65±0.51*

0.24±0.200.37±0.31*

0.040.008

0.0040.0008

0.040.24

0.240.07

P valueFluvastatin Control

“Fluvastatin may halt the progression of coronary atherosclerosis by the reduction of fibro-fatty.”


0 1 3 6

480848: 160 mg

Placebo12 months

imagingbiomarkersendo function

imagingbiomarkers

endo functionbiomarkersendofunction

biomarkersendofunction

ACS/non-ACSLp-PLA2 inhibitor(Darapladib)

Multicenter, randomized, double-blind, parallel-group, placebo-controlled treatment trial in 330 patients with non-

culprit CAD

All patients on standard medical therapy !!!

Overall Design

IBIS 2 (Europe)(Integrated Biomarkers and Imaging Study)

Serruys PW et al. Circulation 2008; 118: 1172–82.


0.003-1.2±4.90.9±6.6∆NC vol, mm3

0.450.006P**

0.710.009P**

0.0080.16P**

Worst 10mm

0.0470.5±7.62.5±9.6∆NC, %

0.012-0.5±13.94.5±17.9∆NC vol, mm3

Region of interest

P*Darapladib Placebo

Serial Necrotic Core Measurement between baseline and 12 month

*P; between group comparison **P; within group comparison

“Despite standard-of-care medical Tx, NC continued to expand in placebo group, but darapladibprevented NC expansion”


JUPITOR Trial

“Suggested Plausible Mechanism of Statin to Reduce Major Cardiovascular Events was

Plaque Stabilization ”


Statin-naïve patients with angiographically documented mild to moderate coronary disease(Total 312 patients needed)

Rosuvastatin 40mg (n=208)

2:1 randomization (double-blinded)

**Primary end point: % compositional change of coronary plaque from baseline to 12-months follow-up.

VH-IVUS, Conventional IVUS, and OCT follow-up at 12 monthsClinical follow-up at 12 months

Rosuvastatin 10mg (n=104)

The STABLE trial (STatin and Atheroma VulneraBiLity Evaluation)

: Double-blinded, Prospective, Randomized, Controlled Trial


SPECIAL: clinically silent plaque progression

• PIs: Dr Tadanori Aizawa and Dr Etsuo Tsuchikane• Multicenter study on the safety of 3-vessel

VH-IVUS interrogation, clinical event rate and silent plaque progression of angiographically intermediate lesions in ACS patients

• Angiographic and IVUS follow-up at 1 year• All sites: Japan• n=300• Status: Enrolling


ATLANTAAssessment of Tissue characteristics, Lesion morphology and hemodynamics by Angiography with fractional flow reserve, intravascular ultrasound and virtual histology and Non-invasive computed

Tomography in Atherosclerotic plaques

the correlation with VH IVUS and FFR with a non-invasive MSCT

• PI Dr S Voros• Single center registry with one year clinical

outcome (MACE) of intermediate lesions by angiogram and diagnostic correlation with further assessment by FFR, MSCT and grayscale and VH IVUS

• N=300• Enrolling


• VH Findings showed good correlation with known risk factors, blood biomarker, clinical presentation, and pathologic plaque composition suggested in previous literatures.

• Ongoing clinical study will provide the information regarding the impact of VH-findings on future clinical outcomes (PROSPECT, SPECIAL, ATLANTA)

• VH-vulnerability may also be surrogate target marker for plaque stabilization or regression (IBIS-1, IBIS-2, STABLE)

Current Clinical Study Results and Future Study Perspective

Overall Summary

virtual histology; clinical applicability · cardiovascular research foundation asan medical center...

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